Mark Crawford, Contributing Writer03.04.21
COVID-19 created exceptional demand for medical device testing in 2020 and this trend will continue throughout 2021. Much of the investigative and R&D work conducted by medical device manufacturers (MDMs) ceased during the first half of 2020, but is starting to return now that the industry has learned how to operate during the pandemic. Due to lost time last year, there is a big rush on testing services and timelines will have to be extended in most cases.
“Many of the postponed projects have picked back up and the industry is trying to accelerate and get back on track,” said Maciej Jakucki, medical device testing manager for Element Materials Technology, a Cincinnati, Ohio-based provider of testing services for medical, pharmaceutical, and diagnostic devices. “The last three months in the medical space have been as busy as we have ever seen it.”
The impact of COVID-19 has been massive. Laboratory work cannot be done remotely. Even with personal protective equipment (PPE), laboratory staff are handling carcinogens, mutagens, toxins, and sensitizers. Many procedures require lab staff to be in close contact for extended periods of time. “Even when lab coats, gloves, masks, face shields, and goggles are worn, and labs are cycling 100-percent fresh air every four minutes, if someone contracts COVID-19, the entire department can be closed for two to three weeks through contact tracing,” said Laurence Lister, director of biocompatibility services for Toxikon Corporation, a Bedford, Mass.-based contract research organization specializing in biocompatibility evaluations of medical devices.
The vast majority of medical equipment being tested is PPE—in part because there is reduced demand for medical devices (fewer scheduled surgeries, a result of the coronavirus).
“PPE is now consistently expedited to get these products out to the front-line healthcare workers,” added Lister.
“As a result,” said Audrey Turley, senior biocompatibility expert for Nelson Labs, a Salt Lake City, Utah-based contract research organization that provides microbiological, analytical, and biological testing services to medical device manufacturers and pharmaceutical companies, “we have seen validation work in other areas drop off as many companies are focusing on current demand due to the pandemic, rather than working on innovative technology.”
PPE testing also involves trying to validate the reuse of this equipment, including single-use masks.
“Until the onset of the pandemic last spring, healthcare facemasks were single use,” said Gary Socola, president of HIGHPOWER Validation Testing and Lab Services, a Rochester, N.Y.-based testing facility that validates reusable medical and dental devices. “However, due to the worldwide shortage, many manufacturers are exploring the options to test these masks for multiple uses. These tests include sterilization, adherence to original filtration specifications, and fitment testing.”
Advisory services with testing firms are fully booked as MDMs hurry to be ready for the new EU Medical Device Regulation (MDR), which takes effect in May 2021 (originally scheduled for May 2020, the MDR deadline was extended one year due to the global pandemic). “Medical device companies are scrambling to perform the required testing so they can be compliant with the new EU MDR to avoid products being withdrawn beyond May of this year,” said Weixi Liu, study director for Jordi Labs, a Mansfield, Mass.-based laboratory that provides a variety of testing services, including extractables and leachables (E&L) testing, for the medical device industry.
Add the recent release of the new ISO 10993-18:2020 standard and the need for regulatory testing services has never been greater.
“Companies have spent the year-long delay in MDR trying to catch up on any gaps,” said Thor Rollins, senior director of E&L consulting for Nelson Labs. “This mostly focuses on biocompatibility and E&L testing. Right now, we are seeing large delays from the labs that perform this testing.”
Latest Trends
Chemical characterization and E&L requirements are in high demand as MDMs pay more attention to toxicology, residuals, and overall product characterization. “There are many questions on the best approach and comparing previous thought patterns of ‘testing for everything’ versus really evaluating the manufacturing steps and potential risks,” said Jakucki.
The explosive increase in chemistry testing is also related to its use as an alternative to animal testing for implantable devices. In October 2020, the FDA proposed a draft document on “Select Updates for Biocompatibility of Certain Devices in Contact with Intact Skin.” This is an exciting option for manufacturers of Class I devices made of common materials such as acrylonitrile butadiene styrene (ABS) or polyetheretherketone (PEEK) to have direct discussions about the reduced risk of these materials from a biocompatibility perspective. If this communication results in less testing, it will cut costs for these companies, especially through reduced need for animal testing, which will save thousands of animals each year. “This is a perfect example of assessing devices and materials from a risk-based approach and applying what we already know from decades of similar applications,” said Turley.
Other top demands for medical testing include COVID-19 vaccines and their distribution systems, ventilators, and other systems. In particular, there has been extra attention from regulatory agencies on breathing gas pathway devices. “This may be because the ISO 18562 standards are finally coming into their own, or that COVID-19 has precipitated the increased scrutiny,” said Christopher Pohl, associate toxicologist for Nelson Labs.
“Barrier testing for PPE has increased over 600 percent, demanding the operation of the laboratory 24 hours a day, seven days a week,” added Turley.
The increased complexity and diversity of medical devices has increased the need for sophisticated, specific equipment for testing each component and the overall function of the completed device. Changing and increasingly complex regulations are driving the need to validate equipment and processes. “For instance, universal test systems designed to test drug delivery systems are improving capabilities and reducing lead times for testing,” said Matt Pasma, test engineer for DDL, an Eden Prairie, Minn.-based provider of package, product, and materials testing for the medical device and pharmaceutical industries. “These systems have newer technologies that allow more control with increased measurement precision during each test.”
This is something that Kumar Rupesh, senior manager for finance and operation for FUTEK Advanced Sensor Technology, an Irvine, Calif.-based provider of standard and custom load, force, torque, and pressure testing, has also observed, especially for surgical robotics, tactical control, advanced surgical instrument maneuverability, and exoskeletons—all of which are on the verge of explosive growth and pushing the boundaries of geometric tolerance.
“The advancement of these systems and devices relies a great deal on advancements in load, torque, and pressure sensor technology, as well as related electronics,” said Rupesh. “As an increasing number of equipment manufacturers seek direct measurement over indirect, and quality/durability requirements are becoming more stringent, our customer and application base continues to grow in all product categories.”
What OEMs Want
MDMs want to catch up on their delayed testing needs and be ready for the rollout of the new EU MDR. This requires plenty of testing and support from their lab partners, especially in-depth discussions regarding the General Safety and Performance Requirement (GSPR) 10.4.1 regarding carcinogens, mutagens, and reproductive toxins.
Breathing circuit and gas pathway device testing is in especially high demand. OEMs are also asking for end-of-life assessments, especially for devices that come into contact with the patient. For example, blood-contacting devices such as catheters and vascular stents require special consideration regarding any possible changes in surface characteristics over time that may alter the interaction of the device with the blood. “Another important consideration is reprocessed devices,” said Turley. “There is a need to ensure these devices are not only clean and sterile for every cycle of use, but still biocompatible, ensuring that materials have not changed over time due to the reprocessing.”
Socola indicated sterilization validations and cleaning validations of reusable medical devices are among HIGHPOWER’s most high-demand tests, followed by material compatibility testing of reusable devices. The FDA continues to request more data on the usable life for a device. “This requires more reprocessing studies of a reusable device to determine if any degradation occurs after its cleaning, packaging, or repeated sterilization,” said Socola.
There are also numerous requests for testing syringes, auto-injectors, medical connectors, and packaging validations, as well as medical connector testing under the ISO 80369 standard. “We continue to receive many testing requests for pre-filled syringes, auto-injectors, and pen injectors,” said Pasma. “This testing largely focuses on physical and mechanical performance to measure attributes such as leakage, break loose, extrusion force, and burst resistance as outlined in the ISO 11040 and ISO 11608 series of standards.”
The rapidly growing injectable market has also revealed the need for more accurate container closure integrity (CCI) testing to meet USP-NF<1207> deterministic CCI requirements. Many of these combination products also require ISO 11607 package validations.
Pushing the Limits of Technology
Over the course of 2020, expectations by the FDA for chemical characterization increasingly push the limits of testing technology. For example, in 2018, inclusion of liquid chromatography with high-resolution accurate mass spectroscopy (LC/HRAM) was considered optional. The following year, this method was viewed more as a requirement and it was common to have a challenging threshold sensitivity of 1.5 µg/device for screening studies. Today, the FDA is asking for a factor of 10 lower.
“We get the feeling the FDA is asking for beyond the theoretical limit of science to try and figure out just how far labs can go,” commented Matthew R. Jorgensen, materials scientist and toxicologist for Nelson Labs.
FUTEK Advanced Sensor Technology continues to advance the capabilities of its nano sensors, which push the size constraint boundaries for strain gauge technology. These load cells have dimensions in the millimeter range that deliver highly accurate and repeatable strain readings for applications with extremely small footprints, such as surgical instruments. The company is also working to integrate its nano sensors with miniature embedded electronics, including wireless and ethernet applications. “Our recent nano-connect design and standard quick-disconnects allow the customers to replace and extend the sensor or cable as needed,” said Rupesh.
One of the required tests for products that come in contact with blood is the rabbit pyrogen test. This test demonstrates if a product has the ability to raise body temperature to a point that appears to be a septic reaction, which requires the restraint of rabbits to have rectal temperatures taken. Toxikon is in the process of validating a new process where rabbits are implanted with internal temperature probes that can be read, without the need to disturb or restrain the animals. “This is uncharted territory and we don’t know how it will be accepted,” said Lister. “However, it is a big improvement in the realm of animal welfare and we are optimistic it will be well-received.”
There is also a shift in how software is used, with a push toward more audit trails that ensure data integrity is maintained throughout the entire testing process. Laboratory information management systems [LIMS] and other specific add-on software make it easier to generate the exact data the FDA and other regulatory bodies request to validate traceability. “For example, web cameras are often used to record testing, which can be played back to review particular points of interest frame by frame,” said Pasma. “Videos can also be stored and sent electronically for use in reporting. We have also seen a need for mapping a device to ensure it will show up on X-rays and other medical scans to ensure its location is correct in the body.”
“There is an increased focus on how electronic data is handled in the laboratory,” agreed Christopher Scott, vice president for Eurofins Medical Device Testing, a global provider of testing for Class I, II, and III medical devices and validation for product designs. “It is expected that any data generated in a laboratory setting must meet ALCOA+ [a framework that requires data to be attributable, legible, contemporaneous, original, and accurate] principles,” said Scott. “Eurofins Medical Device Testing maintains a team of IT specialists whose sole responsibility is ensuring the company’s proprietary LIMS system, as well as the wide range of software-driven equipment and operating systems that interface with it, meet and exceed data integrity requirements.”
IoT and AM
More devices are utilizing electronics. Interfaces for devices that previously relied on a hard cable connecting them to a monitor or terminal are now being developed for Bluetooth or wireless transmission of the data. This creates significant data security issues, which sometimes almost seems like an afterthought for some MDMs. As wireless technologies are integrated into an increasing variety of devices at record rates, regulations often lag behind or are constantly evolving. Also, off-the-shelf electronics may require a higher level of testing and certification if they are integrated into a medical device. The MDM is ultimately responsible for compliance when integrating a wireless device or radio into a product, regardless of whether that device is certified or not.
The FDA has made it clear the cybersecurity risks of electronic devices must be formally assessed as part of the development plan. “Although cybersecurity is usually associated with devices that communicate via the internet, vulnerabilities must be assessed for any device whose embedded circuitry can be accessed, for example through WiFi, LANs, flash drives, or the device’s user interfaces,” said Scott.
Additive manufacturing (AM) continues to bring new challenges to testing. Many MDMs use AM for making prototypes and obtaining performance data before launching full-scale production. Finding the correct material for additive manufacturing is especially important. For example, when AM-made devices are exposed to extreme temperatures and humidities, they react differently. “Just because it is durable at room temperature does not mean it will last after an accelerated aging cycle or an environmental conditioning cycle, where it is subjected to temperatures of 55°C to 80°C or even extreme cold,” said Pasma.
Another challenge with 3D-printed materials are the additives used to process the materials. “Regulatory bodies are concerned about manufacturing-dependent residuals and lot-to-lot variability and may call for the entire battery of biological tests, especially for polymeric devices,” said Helin Räägel, a senior biocompatibility expert for Nelson Labs.
There have been more contract manufacturers entering the AM space with different ideas or approaches about validation. ASTM International is continuously working on standardizing and providing guidance, but the pace of AM innovation makes it hard to keep up. AM-printed products must still meet the same criteria as traditional manufactured products, often with the addition of other tests such as mass loss or debris analysis.
“From a materials perspective, build plates and equipment are evaluated with the standard tensile, chemistry, density, and porosity measurements and there are additional measurements required for coupon testing,” said Jakucki. “Fortunately, there is more information and collaboration available in the industry today that can help drive timelines forward, making it easier for manufacturers to get started with AM technologies.”
Regulatory Developments
The FDA has released a pilot program that allows test labs to essentially become an extension of the FDA if they pass accreditation. Called the Accreditation Scheme for Conformity Assessment (ASCA), the program involves a two-step accreditation process where a testing laboratory is first accredited by an accreditation body and then the FDA will inspect and possibly accredit the testing laboratory. The goal is for the FDA to have confidence in particular labs, “which will shift a lot of labor from the FDA to qualified contract research organizations, where the real biocompatibility expertise resides,” said Lister.
Over the past year, perhaps the biggest news in the regulatory realm for medical devices was the release of ISO 10993-18:2020 (Biological evaluation of medical devices, Part 18: Chemical characterization of medical device materials within a risk management process stricter requirements). This guidance provides more in-depth discussion around how chemical characterization should be conducted for medical devices. Compared to its predecessor, there are multiple key changes defining the best practice for testing and raising the bar for compliance to a great extent. “A few examples include a strong emphasis on exhaustive extractions for medical devices with long-term patient contact, a more stringent requirement on verifying method suitability including its sensitivity, accuracy, and precision to reach the analytical objectives, and the necessity to tailor the testing strategy by considering materials of construction and product configuration,” said Liu.
ISO 10993-18:2020 quickly became the FDA’s recognized consensus standard. This has prompted a significant increase in the scrutiny of testing strategy, data collection, interpretation, and reporting by the regulatory bodies. “A surge in deficiencies issued by the FDA in the past year across the whole industry was observed, all of which are believed to be driven by the release of ISO 10993-18:2020,” Liu added.
Speed Is of the Essence
MDMs often ask testing labs to meet impossibly short timelines. Some project managers do not realize how long some of these validation studies can be—tests can require the incubation of test samples for two to three weeks. “Then add the time required to set up a test, the protocol writing and signature process, test execution, data gathering, report writing, technical and quality reviews, and then the electronic storage of the data, and finally, the release of the final report to the client,” said Socola. “As an ISO 17025 accredited lab, we must adhere to internal guidelines and the requirements of the standard, which is not always a quick process.”
“Some testing, such as accelerated aging, can only be sped up so much,” added Pasma. “For other testing though, we are dealing with time demands by adding more equipment and staff and working longer hours to complete testing projects.”
Every client project has its own unique set of circumstances. Some companies are startups with limited resources and may not always have the required sample size needed to conduct every test within their allotted timelines. Devices are expensive and sample sizes can be high. Therefore, when designing the many tests needed for a reusable surgical device, with limited samples, a timeline of the tests to minimize the total time to conduct all testing becomes quite the challenge to create. “This is especially true when the same device samples are needed for validation testing in multiple lab departments, whether they [are] needed for sterilization efficacy tests, cleaning or packaging validation, biocompatibility testing, materials compatibly testing, or human factors testing,” said Socola. “Therefore, the logistics of device testing and flow within the internal lab structure is critical to ensure that realistic client timelines are met.”
Due to the untargeted nature of E&L testing, it can be daunting to develop a suitable (and quick) method for detecting compounds with a broad range of chemical/physical properties. Testing laboratories have struggled to achieve the required sensitivity and accuracy without requiring an unmanageable analytical effort, which can create an unreasonable burden in terms of costs and time on MDMs.
To speed up the process, Jordi Labs has developed a multidetector approach that uses a combination of chromatographic methods and detectors for simultaneous detection, identification, and quantification of product impurities. These systems utilize two distinct chromatographic methods—liquid chromatography (LC) and gas chromatography (GC), coupled with multiple detectors including mass spectrometer (MS), ultraviolet detector (UV), charged aerosol detector (CAD), and flame ionization detector (FID). “This method provides a substantial improvement in detection coverage by leveraging distinct detection principles across different detectors,” said Liu. “It saves time and also provides a significant improvement in method accuracy by providing an option for detector optimization during quantification.”
All medical devices sterilized using ethylene oxide (EO) must follow ISO 11135:2014 and, prior to release, the sterilized product must be tested for EO residuals. However, since March 2019, at least seven major sterilization facilities around the U.S. have closed, mostly for violating emission standards. This has created long lead times for new product sterilization validations.
Shorter sterilization lead times are always in demand. Boulder Sterilization Services, a subsidiary of Boulder iQ, a Boulder, Colo.-based provider of design and development services for medical device manufacturers, can shorten lead times by up to six months by running all three main steps—sublethal cycle, microbiological performance qualification, and physical performance qualification—in smaller chambers. The smaller chambers make the sterilization cycles significantly shorter—a total cycle time of eight hours or less compared to two to four days. The handling time of the product and biological indicators is also faster due to the reduced volume of product. “In addition,” said Jim Kasic, founder of Boulder iQ, “the smaller chamber size makes it easier to determine the appropriate validation cycles, allowing these cycles to be run on a more condensed schedule without significant risk. We can also shorten biological indicators incubation times to four hours, compared to the standard of 48 hours.”
Seeing an opportunity to move into a market that is struggling with demand issues and timelines, non-medical or tech companies are making a play in the medical sector. It started with the rush for ventilators, face masks, and other PPE in response to COVID-19. Now these companies are competing with established companies in the testing field and continue to look for new opportunities.
“Companies that had never submitted to the FDA were suddenly rushing through emergency use authorizations and 510(k) submissions,” said Jakucki. “However, now, as a result of this surge, we are combining more mechanical, diagnostic, biological, pharmaceutical, and connected technologies to create products that were not on the horizon 12 months ago. External input from outside companies has always had the potential to jump-start innovation in the medical device sector and, although it took COVID-19 to accelerate it, I think the long-term potential for groundbreaking innovation in the testing field is quite promising.”
Mark Crawford is a full-time freelance business and marketing/communications writer based in Madison, Wis. His clients range from startups to global manufacturing leaders. He also writes a variety of feature articles for regional and national publications and is the author of five books.
“Many of the postponed projects have picked back up and the industry is trying to accelerate and get back on track,” said Maciej Jakucki, medical device testing manager for Element Materials Technology, a Cincinnati, Ohio-based provider of testing services for medical, pharmaceutical, and diagnostic devices. “The last three months in the medical space have been as busy as we have ever seen it.”
The impact of COVID-19 has been massive. Laboratory work cannot be done remotely. Even with personal protective equipment (PPE), laboratory staff are handling carcinogens, mutagens, toxins, and sensitizers. Many procedures require lab staff to be in close contact for extended periods of time. “Even when lab coats, gloves, masks, face shields, and goggles are worn, and labs are cycling 100-percent fresh air every four minutes, if someone contracts COVID-19, the entire department can be closed for two to three weeks through contact tracing,” said Laurence Lister, director of biocompatibility services for Toxikon Corporation, a Bedford, Mass.-based contract research organization specializing in biocompatibility evaluations of medical devices.
The vast majority of medical equipment being tested is PPE—in part because there is reduced demand for medical devices (fewer scheduled surgeries, a result of the coronavirus).
“PPE is now consistently expedited to get these products out to the front-line healthcare workers,” added Lister.
“As a result,” said Audrey Turley, senior biocompatibility expert for Nelson Labs, a Salt Lake City, Utah-based contract research organization that provides microbiological, analytical, and biological testing services to medical device manufacturers and pharmaceutical companies, “we have seen validation work in other areas drop off as many companies are focusing on current demand due to the pandemic, rather than working on innovative technology.”
PPE testing also involves trying to validate the reuse of this equipment, including single-use masks.
“Until the onset of the pandemic last spring, healthcare facemasks were single use,” said Gary Socola, president of HIGHPOWER Validation Testing and Lab Services, a Rochester, N.Y.-based testing facility that validates reusable medical and dental devices. “However, due to the worldwide shortage, many manufacturers are exploring the options to test these masks for multiple uses. These tests include sterilization, adherence to original filtration specifications, and fitment testing.”
Advisory services with testing firms are fully booked as MDMs hurry to be ready for the new EU Medical Device Regulation (MDR), which takes effect in May 2021 (originally scheduled for May 2020, the MDR deadline was extended one year due to the global pandemic). “Medical device companies are scrambling to perform the required testing so they can be compliant with the new EU MDR to avoid products being withdrawn beyond May of this year,” said Weixi Liu, study director for Jordi Labs, a Mansfield, Mass.-based laboratory that provides a variety of testing services, including extractables and leachables (E&L) testing, for the medical device industry.
Add the recent release of the new ISO 10993-18:2020 standard and the need for regulatory testing services has never been greater.
“Companies have spent the year-long delay in MDR trying to catch up on any gaps,” said Thor Rollins, senior director of E&L consulting for Nelson Labs. “This mostly focuses on biocompatibility and E&L testing. Right now, we are seeing large delays from the labs that perform this testing.”
Latest Trends
Chemical characterization and E&L requirements are in high demand as MDMs pay more attention to toxicology, residuals, and overall product characterization. “There are many questions on the best approach and comparing previous thought patterns of ‘testing for everything’ versus really evaluating the manufacturing steps and potential risks,” said Jakucki.
The explosive increase in chemistry testing is also related to its use as an alternative to animal testing for implantable devices. In October 2020, the FDA proposed a draft document on “Select Updates for Biocompatibility of Certain Devices in Contact with Intact Skin.” This is an exciting option for manufacturers of Class I devices made of common materials such as acrylonitrile butadiene styrene (ABS) or polyetheretherketone (PEEK) to have direct discussions about the reduced risk of these materials from a biocompatibility perspective. If this communication results in less testing, it will cut costs for these companies, especially through reduced need for animal testing, which will save thousands of animals each year. “This is a perfect example of assessing devices and materials from a risk-based approach and applying what we already know from decades of similar applications,” said Turley.
Other top demands for medical testing include COVID-19 vaccines and their distribution systems, ventilators, and other systems. In particular, there has been extra attention from regulatory agencies on breathing gas pathway devices. “This may be because the ISO 18562 standards are finally coming into their own, or that COVID-19 has precipitated the increased scrutiny,” said Christopher Pohl, associate toxicologist for Nelson Labs.
“Barrier testing for PPE has increased over 600 percent, demanding the operation of the laboratory 24 hours a day, seven days a week,” added Turley.
The increased complexity and diversity of medical devices has increased the need for sophisticated, specific equipment for testing each component and the overall function of the completed device. Changing and increasingly complex regulations are driving the need to validate equipment and processes. “For instance, universal test systems designed to test drug delivery systems are improving capabilities and reducing lead times for testing,” said Matt Pasma, test engineer for DDL, an Eden Prairie, Minn.-based provider of package, product, and materials testing for the medical device and pharmaceutical industries. “These systems have newer technologies that allow more control with increased measurement precision during each test.”
This is something that Kumar Rupesh, senior manager for finance and operation for FUTEK Advanced Sensor Technology, an Irvine, Calif.-based provider of standard and custom load, force, torque, and pressure testing, has also observed, especially for surgical robotics, tactical control, advanced surgical instrument maneuverability, and exoskeletons—all of which are on the verge of explosive growth and pushing the boundaries of geometric tolerance.
“The advancement of these systems and devices relies a great deal on advancements in load, torque, and pressure sensor technology, as well as related electronics,” said Rupesh. “As an increasing number of equipment manufacturers seek direct measurement over indirect, and quality/durability requirements are becoming more stringent, our customer and application base continues to grow in all product categories.”
What OEMs Want
MDMs want to catch up on their delayed testing needs and be ready for the rollout of the new EU MDR. This requires plenty of testing and support from their lab partners, especially in-depth discussions regarding the General Safety and Performance Requirement (GSPR) 10.4.1 regarding carcinogens, mutagens, and reproductive toxins.
Breathing circuit and gas pathway device testing is in especially high demand. OEMs are also asking for end-of-life assessments, especially for devices that come into contact with the patient. For example, blood-contacting devices such as catheters and vascular stents require special consideration regarding any possible changes in surface characteristics over time that may alter the interaction of the device with the blood. “Another important consideration is reprocessed devices,” said Turley. “There is a need to ensure these devices are not only clean and sterile for every cycle of use, but still biocompatible, ensuring that materials have not changed over time due to the reprocessing.”
Socola indicated sterilization validations and cleaning validations of reusable medical devices are among HIGHPOWER’s most high-demand tests, followed by material compatibility testing of reusable devices. The FDA continues to request more data on the usable life for a device. “This requires more reprocessing studies of a reusable device to determine if any degradation occurs after its cleaning, packaging, or repeated sterilization,” said Socola.
There are also numerous requests for testing syringes, auto-injectors, medical connectors, and packaging validations, as well as medical connector testing under the ISO 80369 standard. “We continue to receive many testing requests for pre-filled syringes, auto-injectors, and pen injectors,” said Pasma. “This testing largely focuses on physical and mechanical performance to measure attributes such as leakage, break loose, extrusion force, and burst resistance as outlined in the ISO 11040 and ISO 11608 series of standards.”
The rapidly growing injectable market has also revealed the need for more accurate container closure integrity (CCI) testing to meet USP-NF<1207> deterministic CCI requirements. Many of these combination products also require ISO 11607 package validations.
Pushing the Limits of Technology
Over the course of 2020, expectations by the FDA for chemical characterization increasingly push the limits of testing technology. For example, in 2018, inclusion of liquid chromatography with high-resolution accurate mass spectroscopy (LC/HRAM) was considered optional. The following year, this method was viewed more as a requirement and it was common to have a challenging threshold sensitivity of 1.5 µg/device for screening studies. Today, the FDA is asking for a factor of 10 lower.
“We get the feeling the FDA is asking for beyond the theoretical limit of science to try and figure out just how far labs can go,” commented Matthew R. Jorgensen, materials scientist and toxicologist for Nelson Labs.
FUTEK Advanced Sensor Technology continues to advance the capabilities of its nano sensors, which push the size constraint boundaries for strain gauge technology. These load cells have dimensions in the millimeter range that deliver highly accurate and repeatable strain readings for applications with extremely small footprints, such as surgical instruments. The company is also working to integrate its nano sensors with miniature embedded electronics, including wireless and ethernet applications. “Our recent nano-connect design and standard quick-disconnects allow the customers to replace and extend the sensor or cable as needed,” said Rupesh.
One of the required tests for products that come in contact with blood is the rabbit pyrogen test. This test demonstrates if a product has the ability to raise body temperature to a point that appears to be a septic reaction, which requires the restraint of rabbits to have rectal temperatures taken. Toxikon is in the process of validating a new process where rabbits are implanted with internal temperature probes that can be read, without the need to disturb or restrain the animals. “This is uncharted territory and we don’t know how it will be accepted,” said Lister. “However, it is a big improvement in the realm of animal welfare and we are optimistic it will be well-received.”
There is also a shift in how software is used, with a push toward more audit trails that ensure data integrity is maintained throughout the entire testing process. Laboratory information management systems [LIMS] and other specific add-on software make it easier to generate the exact data the FDA and other regulatory bodies request to validate traceability. “For example, web cameras are often used to record testing, which can be played back to review particular points of interest frame by frame,” said Pasma. “Videos can also be stored and sent electronically for use in reporting. We have also seen a need for mapping a device to ensure it will show up on X-rays and other medical scans to ensure its location is correct in the body.”
“There is an increased focus on how electronic data is handled in the laboratory,” agreed Christopher Scott, vice president for Eurofins Medical Device Testing, a global provider of testing for Class I, II, and III medical devices and validation for product designs. “It is expected that any data generated in a laboratory setting must meet ALCOA+ [a framework that requires data to be attributable, legible, contemporaneous, original, and accurate] principles,” said Scott. “Eurofins Medical Device Testing maintains a team of IT specialists whose sole responsibility is ensuring the company’s proprietary LIMS system, as well as the wide range of software-driven equipment and operating systems that interface with it, meet and exceed data integrity requirements.”
IoT and AM
More devices are utilizing electronics. Interfaces for devices that previously relied on a hard cable connecting them to a monitor or terminal are now being developed for Bluetooth or wireless transmission of the data. This creates significant data security issues, which sometimes almost seems like an afterthought for some MDMs. As wireless technologies are integrated into an increasing variety of devices at record rates, regulations often lag behind or are constantly evolving. Also, off-the-shelf electronics may require a higher level of testing and certification if they are integrated into a medical device. The MDM is ultimately responsible for compliance when integrating a wireless device or radio into a product, regardless of whether that device is certified or not.
The FDA has made it clear the cybersecurity risks of electronic devices must be formally assessed as part of the development plan. “Although cybersecurity is usually associated with devices that communicate via the internet, vulnerabilities must be assessed for any device whose embedded circuitry can be accessed, for example through WiFi, LANs, flash drives, or the device’s user interfaces,” said Scott.
Additive manufacturing (AM) continues to bring new challenges to testing. Many MDMs use AM for making prototypes and obtaining performance data before launching full-scale production. Finding the correct material for additive manufacturing is especially important. For example, when AM-made devices are exposed to extreme temperatures and humidities, they react differently. “Just because it is durable at room temperature does not mean it will last after an accelerated aging cycle or an environmental conditioning cycle, where it is subjected to temperatures of 55°C to 80°C or even extreme cold,” said Pasma.
Another challenge with 3D-printed materials are the additives used to process the materials. “Regulatory bodies are concerned about manufacturing-dependent residuals and lot-to-lot variability and may call for the entire battery of biological tests, especially for polymeric devices,” said Helin Räägel, a senior biocompatibility expert for Nelson Labs.
There have been more contract manufacturers entering the AM space with different ideas or approaches about validation. ASTM International is continuously working on standardizing and providing guidance, but the pace of AM innovation makes it hard to keep up. AM-printed products must still meet the same criteria as traditional manufactured products, often with the addition of other tests such as mass loss or debris analysis.
“From a materials perspective, build plates and equipment are evaluated with the standard tensile, chemistry, density, and porosity measurements and there are additional measurements required for coupon testing,” said Jakucki. “Fortunately, there is more information and collaboration available in the industry today that can help drive timelines forward, making it easier for manufacturers to get started with AM technologies.”
Regulatory Developments
The FDA has released a pilot program that allows test labs to essentially become an extension of the FDA if they pass accreditation. Called the Accreditation Scheme for Conformity Assessment (ASCA), the program involves a two-step accreditation process where a testing laboratory is first accredited by an accreditation body and then the FDA will inspect and possibly accredit the testing laboratory. The goal is for the FDA to have confidence in particular labs, “which will shift a lot of labor from the FDA to qualified contract research organizations, where the real biocompatibility expertise resides,” said Lister.
Over the past year, perhaps the biggest news in the regulatory realm for medical devices was the release of ISO 10993-18:2020 (Biological evaluation of medical devices, Part 18: Chemical characterization of medical device materials within a risk management process stricter requirements). This guidance provides more in-depth discussion around how chemical characterization should be conducted for medical devices. Compared to its predecessor, there are multiple key changes defining the best practice for testing and raising the bar for compliance to a great extent. “A few examples include a strong emphasis on exhaustive extractions for medical devices with long-term patient contact, a more stringent requirement on verifying method suitability including its sensitivity, accuracy, and precision to reach the analytical objectives, and the necessity to tailor the testing strategy by considering materials of construction and product configuration,” said Liu.
ISO 10993-18:2020 quickly became the FDA’s recognized consensus standard. This has prompted a significant increase in the scrutiny of testing strategy, data collection, interpretation, and reporting by the regulatory bodies. “A surge in deficiencies issued by the FDA in the past year across the whole industry was observed, all of which are believed to be driven by the release of ISO 10993-18:2020,” Liu added.
Speed Is of the Essence
MDMs often ask testing labs to meet impossibly short timelines. Some project managers do not realize how long some of these validation studies can be—tests can require the incubation of test samples for two to three weeks. “Then add the time required to set up a test, the protocol writing and signature process, test execution, data gathering, report writing, technical and quality reviews, and then the electronic storage of the data, and finally, the release of the final report to the client,” said Socola. “As an ISO 17025 accredited lab, we must adhere to internal guidelines and the requirements of the standard, which is not always a quick process.”
“Some testing, such as accelerated aging, can only be sped up so much,” added Pasma. “For other testing though, we are dealing with time demands by adding more equipment and staff and working longer hours to complete testing projects.”
Every client project has its own unique set of circumstances. Some companies are startups with limited resources and may not always have the required sample size needed to conduct every test within their allotted timelines. Devices are expensive and sample sizes can be high. Therefore, when designing the many tests needed for a reusable surgical device, with limited samples, a timeline of the tests to minimize the total time to conduct all testing becomes quite the challenge to create. “This is especially true when the same device samples are needed for validation testing in multiple lab departments, whether they [are] needed for sterilization efficacy tests, cleaning or packaging validation, biocompatibility testing, materials compatibly testing, or human factors testing,” said Socola. “Therefore, the logistics of device testing and flow within the internal lab structure is critical to ensure that realistic client timelines are met.”
Due to the untargeted nature of E&L testing, it can be daunting to develop a suitable (and quick) method for detecting compounds with a broad range of chemical/physical properties. Testing laboratories have struggled to achieve the required sensitivity and accuracy without requiring an unmanageable analytical effort, which can create an unreasonable burden in terms of costs and time on MDMs.
To speed up the process, Jordi Labs has developed a multidetector approach that uses a combination of chromatographic methods and detectors for simultaneous detection, identification, and quantification of product impurities. These systems utilize two distinct chromatographic methods—liquid chromatography (LC) and gas chromatography (GC), coupled with multiple detectors including mass spectrometer (MS), ultraviolet detector (UV), charged aerosol detector (CAD), and flame ionization detector (FID). “This method provides a substantial improvement in detection coverage by leveraging distinct detection principles across different detectors,” said Liu. “It saves time and also provides a significant improvement in method accuracy by providing an option for detector optimization during quantification.”
All medical devices sterilized using ethylene oxide (EO) must follow ISO 11135:2014 and, prior to release, the sterilized product must be tested for EO residuals. However, since March 2019, at least seven major sterilization facilities around the U.S. have closed, mostly for violating emission standards. This has created long lead times for new product sterilization validations.
Shorter sterilization lead times are always in demand. Boulder Sterilization Services, a subsidiary of Boulder iQ, a Boulder, Colo.-based provider of design and development services for medical device manufacturers, can shorten lead times by up to six months by running all three main steps—sublethal cycle, microbiological performance qualification, and physical performance qualification—in smaller chambers. The smaller chambers make the sterilization cycles significantly shorter—a total cycle time of eight hours or less compared to two to four days. The handling time of the product and biological indicators is also faster due to the reduced volume of product. “In addition,” said Jim Kasic, founder of Boulder iQ, “the smaller chamber size makes it easier to determine the appropriate validation cycles, allowing these cycles to be run on a more condensed schedule without significant risk. We can also shorten biological indicators incubation times to four hours, compared to the standard of 48 hours.”
Seeing an opportunity to move into a market that is struggling with demand issues and timelines, non-medical or tech companies are making a play in the medical sector. It started with the rush for ventilators, face masks, and other PPE in response to COVID-19. Now these companies are competing with established companies in the testing field and continue to look for new opportunities.
“Companies that had never submitted to the FDA were suddenly rushing through emergency use authorizations and 510(k) submissions,” said Jakucki. “However, now, as a result of this surge, we are combining more mechanical, diagnostic, biological, pharmaceutical, and connected technologies to create products that were not on the horizon 12 months ago. External input from outside companies has always had the potential to jump-start innovation in the medical device sector and, although it took COVID-19 to accelerate it, I think the long-term potential for groundbreaking innovation in the testing field is quite promising.”
Mark Crawford is a full-time freelance business and marketing/communications writer based in Madison, Wis. His clients range from startups to global manufacturing leaders. He also writes a variety of feature articles for regional and national publications and is the author of five books.
